Briefly stated, our preferred working model of ERM activation is as follows. Note that our primary emphasis is on steps 2 and 3 because we view them as key events that are poorly understood but on which we have innovative ideas and promising experimental evidence. Step 1 is the process of cytosolic ERM encountering the plasma membrane. We view the encounter as diffusion driven, with frequent encounters because of the abundance of ERM in cytoplasm. Step 2 is binding of anionic membrane lipids to exposed sites on lobe C (which we term the Initial Lipid Binding Site (ILBS)). This induces a conformational change in that PH-like lobe and a change in electrostatic environment (due to membrane proximity). Those events cause Step 3 and Step 4, two distinguishable events that likely occur concurrently: Step 3 is release by electrostatic repulsion of an acidic flap that had masked the PIP2 binding pocket in lobe A (which we term the Late Lipid Binding Site) and the hydrophobic groove in lobe C. Step 4 is relaxation of the association between the FERM domain and the C-ERMAD. Step 5 is binding of membrane PIP2 to the PIP2 binding pocket unmasked in step 3. Accompanying step 5 are three distinguishable events that may occur concurrently: Step 6 is rotation of the FERM domain relative to the plane of the membrane whose electrostatic repulsion pushes the alpha B helical region away from its stabilizing contact with the landing pad on lobe A and thus promotes jackknife opening of the alpha-helical linker. Step 7 is (optional) binding of tails of transmembrane proteins to the hydrophobic groove. Step 8 is further conformational change in lobe C which completes the release of the FERM/C-ERMAD association started in step 4. Step 8 then enables three additional distinguishable events: Step 9 is (optional) phosphorylation of the C-terminal Thr. Step 10 is (optional) tail association with actin. Step 11 is (optional) association of NHERF-1 or -2 with the NHERF1-binding hydrophobic pocket. Steps 2 and 3 are key events that have not been given much attention in published discussion and investigation of ERM but we view as central events. Therefore we currently investigate those steps. It is important to understand the Initial Lipid Binding Site (ILBS) on ERM which binds to anionic membrane lipid (step 2). There is lack of clarity in the literature about what part of the ERM molecule mediates this binding. The only PIP2 binding site identified by experimentally-determined structure is the IP3-binding pocket formed by a cleft between the A and C lobes. However in inactive ERM this site is masked by a stretch of amino acids which we term the (acidic) flap, visualized in the very important solved structure of intact auto-inhibited insect ERM (2I1K). Since the IP3-binding pocket is masked in the inhibited form, there must be some other region of initial interaction. We propose that initial binding to membrane lipid is via an exposed surface of lobe C, based on three lines of evidence that we have integrated. Based on diverse evidence, we predict that the ILBS is formed by basic residues in a surface patch on the PH-like lobe. We have mutated those residues in moesin and testing their functional importance in such assays as regulation of membrane association in lymphoid cells;contribution to lipid binding in vitro, and contribution to PIP2-induced activation of moesin in vitro Our studies confirm three critical residues and demonstrate they are spatially and functionally distinct from the Late Lipid Binding Site.